tbuckley/cabot-search huggingface dataset:
Estimation of Vaccine Effectiveness of CoronaVac and BNT162b2 Against Severe Outcomes Over Time Among Patients With SARS-CoV-2 Omicron
Authors: Yuchen Wei, Katherine Min Jia, Shi Zhao, Chi Tim Hung, Chris Ka Pun Mok, Paul Kwok Ming Poon, Eman Yee Man Leung, Maggie Haitian Wang, Carrie Ho Kwan Yam, Tsz Yu Chow, Zihao Guo, Eng Kiong Yeoh, Ka Chun Chong
Journal: JAMA Network Open (2023)

Few studies have evaluated the waning of vaccine effectiveness against severe outcomes caused by SARS-CoV-2 Omicron infection. Hong Kong is providing inactivated and mRNA vaccines, but the population had limited protection from natural infections before the Omicron variant emerged.To examine the change in vaccine effectiveness against hospitalization and mortality due to the Omicron variant over time.This case-control study included adults with SARS-CoV-2 Omicron variant infection who died or were hospitalized in Hong Kong from January 1 to June 5, 2022 (ie, case participants), and adults with SARS-CoV-2 Omicron, sampled from the public health registry during the study period (ie, control participants), who were matched to case participants by propensity score.Vaccination status of the individuals.Estimated vaccine effectiveness against death, death or hospitalization, and death among hospitalized patients. Vaccine effectiveness was calculated as 1 - adjusted odds ratio obtained by conditional logistic regression adjusted with covariates for each period following vaccination.There were 32 823 case participants (25 546 [77.8%] ≥65 years; 16 930 [47.4%] female) and 131 328 control participants (100 041 [76.2%] ≥65 years; 66 625 [46.6%] female) in the sample analyzed for the death or hospitalization outcome. Vaccine effectiveness against death or hospitalization was maintained for at least 6 months after the second dose of both CoronaVac (74.0%; 95% CI, 71.8%-75.8%) and BNT162b2 (77.4%; 95% CI, 75.5%-79.0%) vaccines. Vaccine effectiveness against death in those aged 18 to 49 years was 86.4% (95% CI, 85.8%-87.0%) and 92.9% (95% CI, 92.6%-93.2%) for those receiving 2 doses of CoronaVac and BNT162b2, respectively, while for patients aged 80 years or older, it dropped to 61.4% (95% CI, 59.8%-63.2%) and 52.7% (95% CI, 50.2%-55.6%) for CoronaVac and BNT162b2, respectively. Nevertheless, overall vaccine effectiveness against death at 4 to 6 months after the third dose was greater than 90% for CoronaVac, BNT162b2, and the mixed vaccine schedule (eg, mixed vaccines: vaccine effectiveness, 92.2%; 95% CI, 89.2%-95.1%).While vaccines were generally estimated to be effective against severe outcomes caused by SARS-CoV-2 Omicron infection, this analysis found that protection in older patients was more likely to wane 6 months after the second dose. Hence, a booster dose is recommended for older patients to restore immunity. This is especially critical in a setting like Hong Kong, where third-dose coverage is still insufficient among older residents.
Evaluation of Tofacitinib in Primary Sclerosing Cholangitis and Associated Colitis: A Multicenter, Retrospective Study
Authors: Ida Schregel, Guilherme P Ramos, Stephanie Ioannou, Emma Culver, Martti Färkkilä, Christoph Schramm
Journal: Clinical Gastroenterology and Hepatology (2023)

Primary sclerosing cholangitis (PSC) is frequently associated with inflammatory bowel disease (IBD).1 The type of IBD (ulcerative colitis or Crohn's disease) was shown to associate with PSC outcome, but a clear understanding of the pathogenetic link between colitis activity and PSC is lacking.2-4 Tofacitinib, mainly inhibiting the Janus-Kinase (JAK) 1/3 pathway, has been approved for the treatment of ulcerative colitis.5 The aim of this study was to assess the safety and efficacy of tofacitinib in patients with PSC-IBD, including liver and bowel disease outcomes.
Incidence of infection with multidrug-resistant Gram-negative bacteria and vancomycin-resistant enterococci in carriers: a systematic review and meta-regression analysis
Authors: Roel P J Willems, Karin van Dijk, Maria J G T Vehreschild, Lena M Biehl, Johannes C F Ket, Sharon Remmelzwaal, Christina M J E Vandenbroucke-Grauls
Journal: The Lancet Infectious Diseases (2023)
Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer
Authors: Clare M. Adams, Ramkrishna Mitra, Youcai Xiao, Peter Michener, Juan Palazzo, Allen Chao, Jitendra Gour, Joel Cassel, Joseph M. Salvino, Christine M. Eischen
Journal: Cancer Discovery (2023)

Triple-negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROteolysis TArgeting Chimera (PROTAC) to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment. MDM2 loss in p53 mutant/deleted TNBC cells in two-dimensional/three-dimensional culture and TNBC patient explants, including relapsed tumors, causes apoptosis while sparing normal cells. Our MDM2-PROTAC is stable in vivo, and treatment of TNBC xenograft-bearing mice demonstrates tumor on-target efficacy with no toxicity to normal cells, significantly extending survival. Transcriptomic analyses revealed upregulation of p53 family target genes. Investigations showed activation and a required role for TAp73 to mediate MDM2-PROTAC-induced apoptosis. Our data, challenging the current MDM2/p53 paradigm, show MDM2 is required for p53-inactivated TNBC cell survival, and PROTAC-targeted MDM2 degradation is an innovative potential therapeutic strategy for TNBC and superior to existing MDM2 inhibitors.p53-inactivated TNBC is an aggressive, therapy-resistant, and lethal breast cancer subtype. We designed a new compound targeting an unexpected vulnerability we identified in TNBC. Our MDM2-targeted degrader kills p53-inactivated TNBC cells, highlighting the requirement for MDM2 in TNBC cell survival and as a new therapeutic target for this disease. See related commentary by Peuget and Selivanova, p. 1043. This article is highlighted in the In This Issue feature, p. 1027.
Near‐Infrared Light‐Driven Mesoporous SiO<sub>2</sub>/Au Nanomotors for Eradication of <i>Pseudomonas aeruginosa</i> Biofilm
Authors: Tijana Maric, Amalie Løvind, Zhongyang Zhang, Jiayue Geng, Anja Boisen
Journal: Advanced Healthcare Materials (2023)

Bacterial biofilms are linked to several diseases and cause resistant and chronic infections in immune-compromised patients. Nanomotors comprise a new field of research showing a great promise within biomedicine but pose challenges in terms of biocompatibility. Nanomotors propelled by thermophoresis could overcome this challenge, as they leave no waste product during propulsion. In this study, mesoporous-silica nanoparticles are coated with a thin layer of gold to make nanomotors, which can be driven by near-infrared (NIR) light irradiation. The prepared mesoporous SiO
Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm
Authors: Jette J. Bakhuizen, Saskia M. J. Hopman, Machteld I. Bosscha, Charlotte J. Dommering, Marry M. van den Heuvel-Eibrink, Janna A. Hol, Lennart A. Kester, Marco J. Koudijs, Karin P. S. Langenberg, Jan L. C. Loeffen, Jasper van der Lugt, Annette C. Moll, Max M. van Noesel, Stephanie E. Smetsers, Evelien de Vos-Kerkhof, Johannes H. M. Merks, Roland P. Kuiper, Marjolijn C. J. Jongmans
Journal: JAMA Network Open (2023)

Importance To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking. Objective To describe a national children’s cancer center’s experience in diagnosing CPSs before introducing routine next-generation sequencing. Design, Setting, and Participants This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022. Exposures As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing. Main Outcomes and Measures Detected cancer predisposition syndromes. Results A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role. Conclusions and Relevance In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.
Pathogenicity of Human Anti-PLA2R1 Antibodies in Minipigs: A Pilot Study
Authors: Linda Reinhard, Thorsten Wiech, Aline Reitmeier, Moritz Lassé, Maya Machalitza, Asmus Heumann, Nicoletta Ferru, Desiree Loreth, Marie-Luise Schröder, Arvid Hutzfeldt, Felix R. Stahl, Sven Peine, Hermann-Josef Gröne, Catherine Meyer-Schwesinger, Markus M. Rinschen, Rolf A.K. Stahl, Elion Hoxha
Journal: Journal of the American Society of Nephrology (2023)

Membranous nephropathy (MN) is an autoimmune kidney disease characterized by immune deposits in the glomerular basement membrane. Circulating anti-phospholipase A 2 receptor 1 (PLA 2 R1) antibodies are detectable in 70%-80% of patients with MN, but experimental evidence of pathogenicity has been lacking. This study demonstrates the pathogenicity of human anti-PLA 2 R1 antibodies in minipigs, a model for MN that intrinsically expresses PLA 2 R1 on podocytes. After passive transfer of human anti-PLA 2 R1 antibody-containing plasma from patients with PLA 2 R1-associated MN to minipigs, antibodies were detected in the minipig glomeruli, but not in response to plasma from healthy controls. The minipigs developed histomorphological characteristics of MN, local complement activation in the glomeruli, and low-level proteinuria within 7 days, showing that human anti-PLA 2 R1 antibodies are pathogenic.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2023)

Death Changes the NeighborhoodMany chemotherapies induce cell death in a subset of tumor cells, but there remains a question of whether this death enables survival of the remaining malignant cells.Using patient-derived colorectal cancer organoids treated with the chemotherapy 5-fluorouracil, Schmitt and colleagues found efficient induction of the mechanistic target of rapamycin (mTOR) pathway in surviving cancer cells, specifically, mTOR complex 1 and its indirect target p-S6.Coadministration of the mTOR inhibitor rapamycin and 5-fluorouracil led to synergistic inhibition of cancer cell survival in organoids and xenografts.Through systematic testing in a mouse model of colorectal cancer, the authors showed that mTOR signaling was driven by paracrine release of ATP from dying cells and required the P2X4 receptor.Inhibition of P2X4, like inhibition of mTOR, greatly decreased tumor graft size when combined with 5-floururacl.
The combination of eddy thermal effect of biodegradable magnesium with immune checkpoint blockade shows enhanced efficacy against osteosarcoma
Authors: Jun Ge, Nailin Yang, Yuqi Yang, Hao Yu, Xiaoyuan Yang, Yingjie Wang, Tianyi Wang, Shuning Cheng, Yuanjie Wang, Zhihui Han, Yun Teng, Jun Zou, Huilin Yang, Liang Cheng
Journal: Bioactive Materials (2023)

Osteosarcoma (OS) patients have a poor prognosis due to its high degree of heterogeneity and high rate of metastasis. Magnetic hyperthermia therapy (MHT) combined with immunotherapy is an effective strategy to treat solid and metastatic tumors. Here, we combined biodegradable magnesium (Mg) macroscale rods, which acted as an eddy thermo-magnetic agent under a low external alternating magnetic field, and immunotherapy to achieve a radical cure for OS. The eddy thermal effect (ETE) of the Mg rods (MgR) showed outstanding cytotoxic effects and enhanced the maturation of dendritic cells (DCs), and the mild MHT induced the immunogenic cell death (ICD) in the OS cells. Combined with immune checkpoint blockade (ICB) therapy, we obtained an excellent curative effect against OS, and a further evaluation demonstrated that the local MHT induced by the MgR increased T cells infiltration and the polarization of M1 macrophages. Interestingly, the biodegradable MgR also promoted bone osteogenesis. Our work highlighted the uneven ETE mediated by the biodegradable MgR induced a comprehensive immunologic activation in the OS tumor microenvironment (TME), which would inspire the application of MHT for the effective treatment of OS.
Utilization and Outcomes of Clinically Indicated Invasive Cardiac Care in Veterans with Acute Coronary Syndrome and Chronic Kidney Disease
Authors: Steven D. Weisbord, Maria K. Mor, Harry Hochheiser, Nadejda Kim, P. Michael Ho, Deepak L. Bhatt, Michael J. Fine, Paul M. Palevsky
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Of studies reporting an association of CKD with lower use of invasive cardiac care to treat acute coronary syndrome (ACS), just one accounted for the appropriateness of such care. However, its findings in patients hospitalized nearly 30 years ago may not apply to current practice. In a more recent cohort of 64,695 veterans hospitalized with ACS, CKD was associated with a 32% lower likelihood of receiving invasive care determined to be clinically indicated. Among patients with CKD, not receiving such care was associated with a 1.39-fold higher risk of 6-month mortality. Efforts to elucidate the reasons for this disparity in invasive care in patients with ACS and CKD and implement tailored interventions to enhance its use in this population may offer the potential to improve clinical outcomes. Background Previous studies have shown that patients with CKD are less likely than those without CKD to receive invasive care to treat acute coronary syndrome (ACS). However, few studies have accounted for whether such care was clinically indicated or assessed whether nonuse of such care was associated with adverse health outcomes. Methods We conducted a retrospective cohort study of US veterans who were hospitalized at Veterans Affairs Medical Centers from January 2013 through December 2017 and received a discharge diagnosis of ACS. We used multivariable logistic regression to investigate the association of CKD with use of invasive care (coronary angiography, with or without revascularization; coronary artery bypass graft surgery; or both) deemed clinically indicated based on Global Registry of Acute Coronary Events 2.0 risk scores that denoted a 6-month predicted all-cause mortality ≥5%. Using propensity scoring and inverse probability weighting, we examined the association of nonuse of clinically indicated invasive care with 6-month all-cause mortality. Results Among 34,430 patients with a clinical indication for invasive care, the 18,780 patients with CKD were less likely than the 15,650 without CKD to receive such care (adjusted odds ratio, 0.68; 95% confidence interval, 0.65 to 0.72). Among patients with CKD, nonuse of invasive care was associated with higher risk of 6-month all-cause mortality (absolute risk, 21.5% versus 15.5%; absolute risk difference 6.0%; adjusted risk ratio, 1.39; 95% confidence interval, 1.29 to 1.49). Findings were consistent across multiple sensitivity analyses. Conclusions In contemporary practice, veterans with CKD who experience ACS are less likely than those without CKD to receive clinically indicated invasive cardiac care. Nonuse of such care is associated with increased mortality.
Re: Bilateral Axillary Nodal Uptake on 99mTc-White Blood Cell Study Secondary to COVID-19 mRNA Vaccination
Authors: Won Srwijitalai, Viroj Wiwanitkit
Journal: Clinical Nuclear Medicine (2022)

∗Private Academic Consultant, Dimapur, India [email protected] †Dr D.Y. Patil Medical College, Pune, India Conflicts of interest and sources of funding: none declared.
Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles
Authors: Tuomas O. Lilius, Kristian Nygaard Mortensen, Claire Deville, Terhi J. Lohela, Frederik Filip Stæger, Björn Sigurdsson, Elisabetta M. Fiordaliso, Marko Rosenholm, Chris Kamphuis, Freek J. Beekman, Andreas I. Jensen, Maiken Nedergaard
Journal: Journal of Controlled Release (2023)

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.
Heart Failure in Patients With Cancer Treated With Anthracyclines—Revisiting the Foundation of Cardio-Oncology
Authors: Michael G. Fradley
Journal: JAMA Network Open (2023)

Carolyn M. Larsen, MD; Mariana Garcia Arango, MD; Harika Dasari, MBBS; Maria Arciniegas Calle, MD; Effie Adjei, MD; Juan Rico Mesa, MD; Christopher G. Scott, MS; Carrie A. Thompson, MD; James R. Cerhan, MD, PhD; Tufia C. Haddad, MD; Matthew P. Goetz, MD; Joerg Herrmann, MD; Hector R. Villarraga, MD
Ensuring Global Access to Cancer Medicines: A Generational Call to Action
Authors: Anna J Dare, Arnauld Bayle, Asma Hatoqai, Chemtai Mungo, Diego Gimenez Velilla, Enrique Soto-Perez-de-Celis, Freddy Houéhanou Rodrigue Gnangnon, Melissa Siaw Han Lim, Tlotlo Ralefala, Venus Dadirai Mushininga
Journal: Cancer Discovery (2023)

Essential cancer treatments are not accessible, affordable, or available to patients who need them in many parts of the world. A new Access to Oncology Medicines (ATOM) Coalition, using public-private partnerships, aims to bring essential cancer medicines and diagnostics to patients in low- and lower middle-income countries.
Letter to the Editor: Living donor liver transplantation for people with PSC
Authors: Melina Heinemann, René Adam, Vincent Karam, Christoph Schramm
Journal: Hepatology (2023)

1I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2European Liver Transplant Registry, APHP Hôpital Paul Brousse, Université, Paris-Sud, Inserm U 935, Villejuif, France 3European Reference Network for Hepatological Diseases, Hamburg, Germany 4Martin Zeitz Center for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany Correspondence Christoph Schramm, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Email: [email protected]
Opening the Windows for More Effective and Equitable Cancer Screening
Authors: Katherine L. Kahn
Journal: JAMA Network Open (2023)

Amidst a flurry of documentation about diminished use of health services during the COVID-19 pandemic, the cohort study by Doan et al 1 in this issue of JAMA Network Open analyzed the trajectory of national breast cancer screening and lung cancer screening from the COVID-19 pandemic onset through April 2022.Lower-than-expected cancer screening rates were noted for both lung cancer and breast cancer during the late 2020 national COVID-19 infection rate surge and the Delta and Omicron waves in 2021 and 2022.By recognizing this persistent depression in breast cancer screening and lung cancer screening, Doan et al 1 highlighted missed opportunities to improve cancer stage at diagnosis and survival afforded by screening.Doan et al 1 used national Medicare data to support analyses of mammography to screen for breast cancer and low-dose computerized tomography to screen for lung cancer among eligible beneficiaries, accounting for age, sex, race, ethnicity, comorbidities, Medicaid enrollment, primary care physician relationship, and educational attainment.In light of widely-reported, substantial disparities in screening, this recent, national data set provides opportunities to report on disparities in the use of these cancer screening services.This Invited Commentary considers the measurement of COVID-19's effect on established screening processes and opportunities for improving screening by engaging the individuals and communities most impacted by these depressed screening rates.
Nasal administration of a temozolomide-loaded thermoresponsive nanoemulsion reduces tumor growth in a preclinical glioblastoma model
Authors: Luana Roberta Michels, Flávia Nathiely Silveira Fachel, Roselena Silvestri Schuh, Juliana Hofstätter Azambuja, Priscila Oliveira de Souza, Nicolly Espindola Gelsleichter, Gabriela Spies Lenz, Fernanda Visioli, Elizandra Braganhol, Helder Ferreira Teixeira
Journal: Journal of Controlled Release (2023)